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https://www.readbyqxmd.com/read/29757889/utilizing-t-cell-activation-signals-1-2-and-3-for-tumor-infiltrating-lymphocytes-til-expansion-the-advantage-over-the-sole-use-of-interleukin-2-in-cutaneous-and-uveal-melanoma
#1
René J Tavera, Marie-Andrée Forget, Young Uk Kim, Donastas Sakellariou-Thompson, Caitlin A Creasy, Ankit Bhatta, Orenthial J Fulbright, Renjith Ramachandran, Shawne T Thorsen, Esteban Flores, Arely Wahl, Audrey M Gonzalez, Christopher Toth, Seth Wardell, Rahmatu Mansaray, Laszlo G Radvanyi, Dan S Gombos, Sapna P Patel, Patrick Hwu, Rodabe N Amaria, Chantale Bernatchez, Cara Haymaker
In this study, we address one of the major critiques for tumor-infiltrating lymphocyte (TIL) therapy-the time needed for proper expansion of a suitable product. We postulated that T-cell receptor activation in the first phase of expansion combined with an agonistic stimulation of CD137/4-1BB and interleukin-2 would favor preferential expansion of CD8 TIL. Indeed, this novel 3-signal approach for optimal T-cell activation resulted in faster and more consistent expansion of CD8CD3 TIL. This new method allowed for successful expansion of TIL from cutaneous and uveal melanoma tumors in 100% of the cultures in <3 weeks...
May 11, 2018: Journal of Immunotherapy
https://www.readbyqxmd.com/read/29755469/urinary-peptides-as-a-novel-source-of-t-cell-allergen-epitopes
#2
Ricardo da Silva Antunes, John Pham, Curtis McMurtrey, William H Hildebrand, Elizabeth Phillips, Simon Mallal, John Sidney, Paula Busse, Bjoern Peters, Véronique Schulten, Alessandro Sette
Mouse allergy in both laboratory workers and in inner-city children is associated with allergic rhinitis and asthma, posing a serious public health concern. Urine is a major source of mouse allergens, as mice spray urine onto their surroundings, where the proteins dry up and become airborne on dust particles. Here, we tested whether oligopeptides that are abundant in mouse urine may contribute to mouse allergic T cell response. Over 1,300 distinct oligopeptides were detected by mass spectrometry analysis of the low molecular weight filtrate fraction of mouse urine (LoMo)...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29748739/anticalin-%C3%A2-proteins-as-therapeutic-agents-in-human-diseases
#3
REVIEW
Christine Rothe, Arne Skerra
Anticalin proteins are an emerging class of clinical-stage biopharmaceuticals with high potential as an alternative to antibodies. Anticalin molecules are generated by combinatorial design from natural lipocalins, which are abundant plasma proteins in humans, and reveal a simple, compact fold dominated by a central β-barrel, supporting four structurally variable loops that form a binding site. Reshaping of this loop region results in Anticalin proteins that can recognize and tightly bind a wide range of medically relevant targets, from small molecules to peptides and proteins, as validated by X-ray structural analysis...
May 10, 2018: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://www.readbyqxmd.com/read/29748183/aberrant-lck-signal-via-cd28-co-stimulation-augments-antigen-specific-functionality-and-tumor-control-by-redirected-t-cells-with-pd-1-blockade-in-humanized-mice
#4
Pratiksha Gulati, Julia Rühl, Abhilash Kannan, Magdalena Pircher, Petra Schuberth, Katarzyna Jozefa Nytko, Martin N Pruschy, Simon Sulser, Mark D Haefner, Shawn M Jensen, Alex Soltermann, Wolfgang Jungraithmayr, Maya Eisenring, Thomas Winder, Panagiotis Samaras, Annett Tabor, Rene Rs Stenger, Roger Stupp, Walter Weder, Christoph Renner, Christian Münz, Ulf Petrausch
PURPOSE: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed. EXPERIMENTAL DESIGN: Fibroblast Activation Protein (FAP)-specific CARs with different co-stimulatory domains including CD28, Δ-CD28 (lacking lck binding moiety) or 4-1BB were established...
May 10, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29744298/the-involvement-of-4-1bb-4-1bbl-signaling-in-glial-cell-mediated-hypothalamic-inflammation-in-obesity
#5
Jiye Kim, Yoon-Hee Kwon, Chu-Sook Kim, Thai H Tu, Byung-Sam Kim, Yeonsoo Joe, Hun T Chung, Tsuyoshi Goto, Teruo Kawada, Taesun Park, Myung-Sook Choi, Min-Seon Kim, Rina Yu
Obesity-induced inflammation occurs not only in peripheral tissues but also in areas of the central nervous system. Glial cells such as astrocytes and microglia play crucial roles in obesity-related hypothalamic inflammation, leading to the derangement of energy metabolism and neurodegenerative pathologies. Here, we show that the interaction of 4-1BB/4-1BBL between lipid-laden astrocytes/microglia promotes hypothalamic inflammation in obesity. Stimulation of 4-1BB, a member of the TNF receptor superfamily, and/or its ligand 4-1BBL on astrocytes and/or microglia with a specific agonist resulted in activation of the inflammatory signaling pathway and enhanced production of inflammatory mediators...
May 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/29721382/expression-of-llt1-and-its-receptor-cd161-in-lung-cancer-is-associated-with-better-clinical-outcome
#6
Véronique M Braud, Jérôme Biton, Etienne Becht, Samantha Knockaert, Audrey Mansuet-Lupo, Estelle Cosson, Diane Damotte, Marco Alifano, Pierre Validire, Fabienne Anjuère, Isabelle Cremer, Nicolas Girard, Dominique Gossot, Agathe Seguin-Givelet, Marie-Caroline Dieu-Nosjean, Claire Germain
Co-stimulatory and inhibitory receptors expressed by immune cells in the tumor microenvironment modulate the immune response and cancer progression. Their expression and regulation are still not fully characterized and a better understanding of these mechanisms is needed to improve current immunotherapies. Our previous work has identified a novel ligand/receptor pair, LLT1/CD161, that modulates immune responses. Here, we extensively characterize its expression in non-small cell lung cancer (NSCLC). We show that LLT1 expression is restricted to germinal center (GC) B cells within tertiary lymphoid structures (TLS), representing a new hallmark of the presence of active TLS in the tumor microenvironment...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29720399/crystal-structure-of-the-human-4-1bb-4-1bbl-complex
#7
Ryan N Gilbreth, Vaheh Y Oganesyan, Hamza Amdouni, Shabazz Novarra, Luba Grinberg, Arnita Barnes, Manuel Baca
4-1BBL is a member of the TNF superfamily and is the ligand for the TNFRsuperfamily receptor, 4-1BB. 4-1BB plays an immunomodulatory role in T cells and NK cells and agonists of this receptor have garnered strong attention as potentialimmunotherapy agents. Broadly speaking, the structural features of TNF superfamilymembers, their receptors and ligand/receptor complexes are similar. However, apublished crystal structure of human 4-1BBL suggests that it may be unique in thisregard, exhibiting a three-bladed propeller-like trimer assembly that is distinctly different from that observed in other family members...
May 2, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29720398/crystal-structures-of-the-human-4-1bb-receptor-bound-to-its-ligand-4-1bbl-reveal-covalent-receptor-dimerization-as-a-potential-signaling-amplifier
#8
Aruna Bitra, Tzanko Doukov, Michael Croft, Dirk M Zajonc
Human (h)4-1BB (TNFRSF9 or CD137) is an inducible tumor necrosis factor receptor (TNFR) super family member that interacts with its cognate ligand h4-1BBL to promote T lymphocyte activation and proliferation. h4-1BB is currently being targeted with agonists in cancer immunotherapy. Here, we determined the crystal structures of unbound h4-1BBL and both wildtype h4-1BB and a dimerization-deficient h-41BB mutant (C121S) in complex with h4-1BBL at resolutions between 2.7 Å and 3.2 Å. We observed that the structural arrangement of 4-1BBL, both unbound and in the complex, represents the canonical bell shape as seen in other similar TNF proteins and differs from the previously reported three-bladed propeller structure of 4-1BBL...
May 2, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29700053/tk-inhibitor-pazopanib-primes-dcs-by-downregulation-of-the-%C3%AE-catenin-pathway
#9
Ilaria Grazia Zizzari, Chiara Napoletano, Andrea Botticelli, Salvatore Caponnetto, Fabio Calabrò, Alain Gelibter, Aurelia Rughetti, Ilary Ruscito, Hassan Rahimi, Ernesto Rossi, Giovanni Schinzari, Paolo Marchetti, Marianna Nuti
Tyrosine kinase inhibitors (TKIs) target angiogenesis by affecting, for example, the VEGF receptors in tumors and have improved outcomes for patients with metastatic renal cell carcinoma (mRCC). Immune checkpoint inhibitors (ICIs) have also been proposed for treatment of mRCC with encouraging results. A better understanding of the activity of immune cells in mRCC, the immuneomodulatory effects of TKIs, and the characteristics defining patients most likely to benefit from various therapies will help optimize immunotherapeutic approaches...
April 26, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29697202/increased-soluble-cd137-levels-and-cd4-t-cell-associated-expression-of-cd137-in-acute-atherothrombotic-stroke
#10
Yang He, Dong-Hui Ao, Xiao-Qing Li, Shan-Shan Zhong, Rong A, Yang-Yang Wang, Ya-Juan Xiang, Bao-Lei Xu, Ting-Ting Yang, Xu-Guang Gao, Guang-Zhi Liu
As a proinflammatory cytokine, CD137 (4-1BB, TNFRSF9) is present in membrane-bound and soluble forms. Increased expression of CD137 was recently found in T cells in human atherosclerotic plaques. However, the exact role of CD137 in ischemic stroke is not clear. In this study we analyzed the protein levels of soluble CD137 (sCD137) and the expression of CD137 on CD4+ T cells in the peripheral blood of patients with acute atherothrombotic stroke by using the cytometry beads array (CBA) and flow cytometry. Within 24 hours of onset, the stroke patients showed elevated levels of sCD137 (2...
April 26, 2018: Clinical and Translational Science
https://www.readbyqxmd.com/read/29679278/overexpression-of-modified-human-tr%C3%AE-1-suppresses-the-growth-of-hepatocarcinoma-sk-hep1-cells-in-vitro-and-in-xenograft-models
#11
Xiaoxiang Peng, Yuntao Zhou, Yanli Sun, Wei Song, Xiangying Meng, Chunling Zhao, Ronglan Zhao
Association studies suggest that TRβ1 functions as a tumor suppressor. Thyroid hormone receptors (TRs) mediate transcriptional responses through a highly conserved DNA-binding domain (DBD). We previously constructed an artificially modified human TRβ1 (m-TRβ1) via the introduction of a 108-bp exon sequence into the corresponding position of the wild-type human TRβ1 (TRβ1) DBD. Studies confirmed that m-TRβ1 was functional and could inhibit the proliferation of breast cancer MDA-MB-468 cells in vitro. To understand the role of m-TRβ1 in liver tumor development, we adopted a gain-of-function approach by stably expressing TRβ (m-TRβ1 and TRβ1) genes in a human hepatocarcinoma cell line, SK-hep1 (without endogenous TRβ), and then evaluated the effects of the expressed TRβ on cancer cell proliferation, migration, and tumor growth in cell-based studies and xenograft models...
April 20, 2018: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/29678874/mitochondrial-morphological-and-functional-reprogramming-following-cd137-4-1bb-co-stimulation
#12
Alvaro Teijeira, Sara Labiano, Saray Garasa, Inaki Etxeberria, Eva Santamaria, Ana Rouzaut, Michel Enamorado, Arantza Azpilikueta, Susana Inoges, Elixabet Bolanos-Mateo, Maria Angela Aznar, Alfonso R Sanchez-Paulete, David Sancho, Ignacio Melero
T and NK lymphocytes express CD137 (4-1BB), a costimulatory receptor of the TNFR family whose function is exploitable for cancer immunotherapy. Mitochondria regulate the function and survival of T lymphocytes. Herein, we show that CD137 costimulation provided by agonist mAb and CD137L (4-1BBL) induced mitochondria enlargement that resulted in enhanced mitochondrial mass and transmembrane potential in human and mouse CD8+ T cells. Such mitochondrial changes increased T-cell respiratory capacities and were critically dependent on mitochondrial fusion protein OPA-1 expression...
April 20, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29627062/immune-active-cells-with-4-1bb-signal-enhancement-inhibit-hepatitis-b-virus-replication-in-noncytolytic-manner
#13
Lili Wang, Yongxiang Yi, Wenxiu Jiang, Dandan Yin, Jing Fan, Wei Ye, Wei Zhao
Immune active cells (IACs) have been shown to be an alternative immunotherapy for CHB patients. However, there is a practical problem of different expansion rate and function of HBV inhibition as individual variability exists. Our previous studies have confirmed that the proliferation and cytolysis of IACs were significantly up-regulated by engineered cells for costimulatory enhancement (ECCE) delivering a 4-1BBζ activating signal. In this study, we aimed to investigate the contribution of ECCE to IACs from CHB patients...
April 2, 2018: Cellular Immunology
https://www.readbyqxmd.com/read/29605883/induction-of-a-central-memory-and-stem-cell-memory-phenotype-in-functionally-active-cd4-and-cd8-car-t-cells-produced-in-an-automated-good-manufacturing-practice-system-for-the-treatment-of-cd19-acute-lymphoblastic-leukemia
#14
Franziska Blaeschke, Dana Stenger, Theresa Kaeuferle, Semjon Willier, Ramin Lotfi, Andrew Didier Kaiser, Mario Assenmacher, Michaela Döring, Judith Feucht, Tobias Feuchtinger
Relapsed/refractory B-precursor acute lymphoblastic leukemia (pre-B ALL) remains a major therapeutic challenge. Chimeric antigen receptor (CAR) T cells are promising treatment options. Central memory T cells (Tcm) and stem cell-like memory T cells (Tscm) are known to promote sustained proliferation and persistence after T-cell therapy, constituting essential preconditions for treatment efficacy. Therefore, we set up a protocol for anti-CD19 CAR T-cell generation aiming at high Tcm/Tscm numbers. 100 ml peripheral blood from pediatric pre-B ALL patients was processed including CD4+ /CD8+ -separation, T-cell activation with modified anti-CD3/-CD28 reagents and transduction with a 4-1BB-based second generation CAR lentiviral vector...
March 31, 2018: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29562451/-an-experimental-study-of-cd4-targeted-chimeric-antigen-receptor-modified-t-cell-with-anti-lymphoma-activity
#15
G H Chen, H W Huang, Y Wang, H W Liu, L J Xu, X Ma, S L Xue, X F He, Y Wang, B Gu, C X Li, H Y Qiu, X W Tang, Z M Jin, M Miao, A N Sun, D P Wu
Objective: To study the specific killing effect of CD4 membrane protein targeted chimeric antigen receptor modified T (CAR-T) cell. Methods: The second generation CD4 targeted chimeric antigen receptor containing 4-1BB costimulation domain was insert into lentiviral vector through recombinant DNA technology. Lentivirus was prepared and packaged by 293T cells with four plasmids. Beads activated T cells were transduced with lentivirus and the transduction efficiency was checked with Protein L and flow cytometry...
February 14, 2018: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/29549159/phase-i-study-of-single-agent-utomilumab-pf-05082566-a-4-1bb-cd137-agonist-in-patients-with-advanced-cancer
#16
Neil H Segal, Aiwu R He, Toshihiko Doi, Ronald Levy, Shailender Bhatia, Michael J Pishvaian, Rossano Cesari, Ying Chen, Craig B Davis, Bo Huang, Aron D Thall, Ajay K Gopal
Purpose: Utomilumab (PF-05082566) is an agonistic mAb that engages the immune costimulatory molecule 4-1BB/CD137. In this first-in-human, phase I, open-label, multicenter, multiple-dose study (NCT01307267) we evaluated safety, tolerability, pharmacokinetics, preliminary clinical activity, and pharmacodynamics of single-agent utomilumab in patients with advanced malignancies. Experimental Design: Dose escalation was based on a standard 3+3 design for doses of utomilumab from 0.006 to 0.3 mg/kg every 4 weeks and a time-to-event continual reassessment method for utomilumab 0...
April 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29544515/next-generation-of-immune-checkpoint-therapy-in-cancer-new-developments-and-challenges
#17
REVIEW
Julian A Marin-Acevedo, Bhagirathbhai Dholaria, Aixa E Soyano, Keith L Knutson, Saranya Chumsri, Yanyan Lou
Immune checkpoints consist of inhibitory and stimulatory pathways that maintain self-tolerance and assist with immune response. In cancer, immune checkpoint pathways are often activated to inhibit the nascent anti-tumor immune response. Immune checkpoint therapies act by blocking or stimulating these pathways and enhance the body's immunological activity against tumors. Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1(PD-L1) are the most widely studied and recognized inhibitory checkpoint pathways...
March 15, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29511066/4-1bb-costimulation-induces-t-cell-mitochondrial-function-and-biogenesis-enabling-cancer-immunotherapeutic-responses
#18
Ashley V Menk, Nicole E Scharping, Dayana B Rivadeneira, Michael J Calderon, McLane J Watson, Deanna Dunstane, Simon C Watkins, Greg M Delgoffe
Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to these therapies. The tumor microenvironment can impose metabolic restrictions on T cell function, creating a resistance mechanism to immunotherapy. We have previously shown tumor-infiltrating T cells succumb to progressive loss of metabolic sufficiency, characterized by repression of mitochondrial activity that cannot be rescued by PD-1 blockade. 4-1BB, a costimulatory molecule highly expressed on exhausted T cells, has been shown to influence metabolic function...
April 2, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29503204/in-vivo-expansion-and-antitumor-activity-of-coinfused-cd28-and-4-1bb-engineered-car-t-cells-in-patients-with-b-cell-leukemia
#19
Zhi Cheng, Runhong Wei, Qiuling Ma, Lin Shi, Feng He, Zixiao Shi, Tao Jin, Ronglin Xie, Baofeng Wei, Jing Chen, Hongliang Fang, Xiaolu Han, Jennifer A Rohrs, Paul Bryson, Yarong Liu, Qi-Jing Li, Bo Zhu, Pin Wang
Several recent clinical trials have successfully incorporated a costimulatory domain derived from either CD28 or 4-1BB with the original CD3ζ T cell activating domain to form second-generation chimeric antigen receptors (CARs) that can increase the responsiveness and survival of CAR-engineered T (CAR-T) cells. However, a rigorous assessment of the individual benefits of these costimulatory components relative to the in vivo performance of infused T cells in patients is still lacking. Therefore, we have designed a study that allows us to investigate and compare the impact of different costimulatory signal domains on CAR-T cells in vivo...
April 4, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29503042/engrafting-human-regulatory-t-cells-with-a-flexible-modular-chimeric-antigen-receptor-technology
#20
Stefanie Koristka, Alexandra Kegler, Ralf Bergmann, Claudia Arndt, Anja Feldmann, Susann Albert, Marc Cartellieri, Armin Ehninger, Gerhard Ehninger, Jan Moritz Middeke, Martin Bornhäuser, Marc Schmitz, Jens Pietzsch, Katja Akgün, Tjalf Ziemssen, Jörg Steinbach, Michael P Bachmann
As regulatory T cells (Tregs) play a fundamental role in immune homeostasis their adoptive transfer emerged as a promising treatment strategy for inflammation-related diseases. Preclinical animal models underline the superiority of antigen-specific Tregs compared to polyclonal cells. Here, we applied a modular chimeric antigen receptor (CAR) technology called UniCAR for generation of antigen-specific human Tregs. In contrast to conventional CARs, UniCAR-endowed Tregs are indirectly linked to their target cells via a separate targeting module (TM)...
June 2018: Journal of Autoimmunity
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